Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors.
CRF has been implicated in psychiatric disorders and neurological diseases including depression and anxiety, as well as the following conditions: Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol and substance abuse and associated withdrawal symptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia, Cushing's disease, hypertension, stroke. irritable bowel syndrome, stress-induced gastric ulceration, premenstrual syndrome, sexual dysfunction, premature labor, inflammatory disorders, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary tumors or ectopic pituitary-derived tumors, chronic fatigue syndrome and fibromyalgia.
CRF receptor subtypes, CRF1 and CRF2, have been identified and are distributed heterogeneously within the brain thereby suggesting potential functional diversity. For example, widely distributed brain CRF1 receptors are strongly implicated in emotionality accompanying exposure to environmental stressors. Significantly, CRF1, not CRF2, receptors appear to mediate select anxiogenic like behaviors. A more discrete septal/hypothalmic distribution and the availability of alternative endogenous ligands suggest a different functional role for the CRF2 receptor. For example, a novel CRF-family neuropeptide with preferential affinity for CRF2 relative to CRF1 receptors is reported to suppress appetite without producing the profile of behavioral activation observed with selective CRF1 agonism. In other cases, CRF2 agonism produces similar effects to those reported for CRF1 antagonists or CRF1 gene deletion. For example, while CRF2 agonists have been proposed as antiobesity agents, CRF1 antagonists may be an important treatment for obesity as well.
Certain pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, pyrazolo[1,5-a]pyrimidines, 1,2,3-triazolo[4,5-b]pyridines, and pyrazolo[1,5-a]-1,3,5-triazines, useful as CRF antagonists, are described in WO 94/13676, WO 97/29109, WO 98/08847, and WO 98/03510.
The present invention provides novel thiophene pyrazolopyrimidines useful as CRF1 receptor antagonists. In view of the above, it is desirable to discover new efficacious and selective antagonists of CRF1 as potentially valuable therapeutic agents for the treatment of psychiatric and neuroendocrine disorders, neurological diseases, and metabolic syndrome. Further, since a majority of commercial CNS and cardiovascular drugs exhibit undesirable bioavailability profiles, it is also desirable to discover new compounds with superior bioavailability profiles relative to known CRF antagonists such as CP154526 and NBI30775.